The use of LCST polymers as controlled release systems is e.g. known from U.S. Pat. No. 5,720,976. In this publication release systems are disclosed, wherein an active ingredient is encapsulated in liposomes. LCST polymers are grafted to the surface of liposomes. By choosing the ratio of respective monomers in the LCST polymers, the LCST value of the polymers can be adjusted.
Furthermore, WO-A-92/07881 discloses that the solubility of polyacrylamide changes as a result of the presence of amide groups, which groups have a buffering effect. This pertains to the solubility per se, not to the LCST, which is not mentioned in this publication.
Also in EP-A-0 693 508 and in DE-A-4 023 578, it is described that the temperature sensitivity of certain polymers can be influenced by varying the ratio of the comonomers present in these certain polymers.
None of these prior art documents teach or suggest however, that LCST polymer systems can be modified, as is done in accordance with the present invention in such a way, that the LCST value of the polymers changes during incubation and as a result of incubation, and by which the above mentioned advantages of the present invention can be obtained.
In WO 01/09198, it is disclosed that a temperature sensitive polymer can be obtained by choosing a monomer that is suitable for the envisaged application, e.g. a monomer that forms a pharmaceutically acceptable polymer. Suitable monomers are the monomers selected from the group comprising ethylene glycol, lactic acid, acrylamide, methacrylamide, acrylic acid, and derivates and substituted species thereof. These monomers and/or other monomers are then reacted under suitable conditions to form homopolymers of one of these monomers or copolymers, terpolymers or other polymers of two or more monomers.
In a preferred embodiment of the invention described in WO 01/09198, the change of solubility characteristics is effected by hydrolysis of a group, such as a lactate, present on at least one of the monomers that form the polymer. In case of an in vivo application such a group can advantageously be an enzymatically or chemically hydrolyzable group. The ester groups are introduced in the polymer by choosing suitable monomers as a starting material. The monomers can be provided with ester groups by techniques known to the person skilled in the art.
In WO 01/09198 the preferred embodiment is based on poly(N-isopropylacrylamide) (PNIPAAm), which has its CP (in water) around 32° C. It is the most extensively studied thermosensitive polymer and is used for the design of thermosensitive drug delivery systems such as polymeric micelles and hydrogels. This polymer has also been used to modify the surface properties of liposomes. The CP of PNIPAAm can be modulated by copolymerising with hydrophobic or hydrophilic comonomers: hydrophobic comonomers decrease the CP whereas hydrophilic comonomers have the opposite effect.
The most preferred thermosensitive polymers of WO 01/09198 are thermosensitive copolymers of NIPAAm and N-(2-hydroxypropyl) methacrylamide lactate (poly(NIPAAm-co-HPMAm-lactate)) and their block copolymers with poly(ethylene glycol) (poly(NIPAAm-co-HPMAm-lactate)-b-PEG). When ≧35 mol % HPMAm-lactate was copolymerised with NIPAAm, these polymers had their CP below body temperature, whereas after hydrolysis of the lactate side chain the CP increased above 37° C. As a result, polymeric micelles formed with poly(NIPAAm-co-HPMAm-lactate)-b-PEG showed controlled instability at body temperature.